Journal of Clinical and Basic Cardiology An Independent International Scientific Journal Journal of Clinical and Basic Cardiology 2001; 4 (1), 53-56 Different beta-blocking effects of carvedilol and bisoprolol in humans Koshucharova G, Klein W, Lercher P, Maier R, Stepan V Stoschitzky K, Zweiker R Homepage: www.kup.at/jcbc Online Data Base Search for Authors and Keywords Indexed in Chemical Abstracts EMBASE/Excerpta Medica Krause & Pachernegg GmbH · VERLAG für MEDIZIN und WIRTSCHAFT · A-3003 Gablitz/Austria ORIGINAL PAPERS, CLINICAL CARDIOLOGY Different Beta-Blocking Effects of Carvedilol and Bisoprolol J Clin Basic Cardiol 2001; 4: 53 Different Beta-Blocking Effects of Carvedilol and Bisoprolol in Humans G. Koshucharova, R. Zweiker, R. Maier, P. Lercher, V. Stepan, W. Klein, K. Stoschitzky Bisoprolol is a beta1-selective beta-adrenergic antagonist while carvedilol is a non-selective beta-blocker with additional blockade of alpha1-adrenoceptors. Administration of bisoprolol has been shown to cause up-regulation of β-adrenoceptor density and to decrease nocturnal melatonin release, whereas carvedilol lacks these typical effects of beta-blocking drugs. The objective of the present study was to investigate beta-blocking effects of bisoprolol and carvedilol in healthy subjects. We compared the effects of single oral doses of clinically recommended amounts of bisoprolol (2.5, 5 and 10 mg) and carvedilol (25, 50 and 100 mg) to those of placebo in a randomised, double-blind, cross-over study in 12 healthy male volun- teers. Three hours after oral administration of the drugs heart rate and blood pressure were measured at rest, after 10 min. of exercise, and after 15 min. of recovery. Bisoprolol tended to decrease heart rate during exercise (–17 %, –21 % and –25 %) to a slightly greater extent than carvedilol (–17 %, –18 % and –21 %) although the differences between the two drugs were not significant. At rest, increasing doses of bisoprolol further decreased heart rates (63, 61 and 53 beats/min) whereas increasing doses of carvedilol resulted in increasing heart rates (63, 63 and 68 beats/min), with 100 mg carvedilol failing to differ significantly from placebo (71 beats/min). We conclude that clinically recommended doses of carvedilol cause clinically relevant beta-blockade in healthy humans predominantly during exercise where it appears to be slightly less effective than bisoprolol. On the other hand, the effects of carvedilol on heart rate at rest appear to be weak or non-existent, particularly in subjects with a low sympathetic tone, whereas bisoprolol is a potent beta-blocker both at rest and during exercise. The weak clinical consequences of beta-blocking effects of carvedilol might possibly be caused by a reflex increase in sympathetic drive due to a decrease in blood pressure resulting from the alpha-blocking effects of the drug. J Clin Basic Cardiol 2001; 4: 53–56. Key words: carvedilol, bisoprolol, beta-blockers, heart failure isoprolol is a selective antagonist of adrenergic β1- pathomimetic activity (ISA) of (R,S)-carvedilol; thirdly, re- B receptors [1] whereas carvedilol is a non-selective β-blocker flex activation of sympathetic tone caused by vasodilation with additional α1-blocking and antioxidant effects [2]. In due to α-blockade of both (R)- and (S)-carvedilol. However, recent years, β-blockers have been shown to be highly effec- ISA was not described with (R,S)-carvedilol [9]. On the tive in the treatment of congestive heart failure (CHF). other hand, in a recent study in healthy subjects who received Carvedilol decreased mortality in large randomised placebo- single oral doses of (R)-, (S)- and (R,S)-carvedilol, the race- controlled studies by 65 % (although not as the primary end mate failed to significantly decrease heart rate, whereas opti- point) [3], whereas bisoprolol did so by 34 % [4]. However, cally pure (R)-carvedilol even slightly increased heart rate it is not known whether or not carvedilol is better than under resting conditions [10], thus supporting our third hy- bisoprolol since the beneficial effects of the two substances in pothesis mentioned above. patients suffering from heart failure have never been investi- In order to address these unsolved issues, we performed a gated in one prospective, randomised, clinical trial. In addi- randomised, double-blind, placebo-controlled, cross-over study tion, it is unclear whether or not there are clinically relevant in 12 healthy volunteers using three doses of (R,S)-carvedilol differences between the β-blocking effects of carvedilol and (25 mg, 50 mg, 100 mg) and (R,S)-bisoprolol (2.5 mg, 5 mg, bisoprolol. Therefore, it appears important to directly com- 10 mg), respectively, which represent the upper range of dos- pare β-blocking effects of carvedilol and bisoprolol in humans. ages recommended for these drugs in clinical practice as well Nearly all β-blockers currently used in research and clini- as those used in the US carvedilol trial [1] and in the CIBIS- cal practice are racemates consisting of (R)- and (S)- II trial [2] to determine clinically relevant β-blocking effects enantiomers in a fixed 1:1 ratio, and all β-blocking potency of (R,S)-carvedilol and (R,S)-bisoprolol in humans. resides exclusively in the (S)-enantiomers whereas the (R)- Throughout the following text, whenever bisoprolol and forms do not contribute to the β-blocking effect of the ra- carvedilol are mentioned without specific reference to the cemic drugs [5]. Chronic administration of β-blockers pro- (R)- and (S)-enantiomers, the commercially available ra- duces reactive up-regulation of β-receptor density [6]. In ad- cemic (R,S)-mixtures were used. dition, β-blockers reduce nocturnal melatonin production [7]. However, carvedilol has been shown neither to cause up- Methods regulation of β-receptor density in some cases [8] nor to in- fluence nocturnal melatonin production [7]. The lack of Study protocol these typical effects of β-blockers in (R,S)-carvedilol is cur- Twelve healthy male volunteers, age 25–42 years, received rently unexplained. However, there are several hypotheses as single oral doses of 25 mg, 50 mg and 100 mg (R,S)-carvedi- to which mechanisms might possibly account for these prop- lol, 2.5 mg, 5 mg and 10 mg (R,S)-bisoprolol, and placebo at erties in carvedilol: Firstly, an insufficient β-blockade by intervals between 3 and 7 days according to a randomised, (R,S)-carvedilol in clinical practice; secondly, intrinsic sym- double-blind, placebo-controlled, cross-over protocol. Prior Received September 25th, 2000; accepted December 19th, 2000. From the Division of Cardiology, Department of Medicine, Karl Franzens University, Graz, Austria Correspondence to: Gergana Koshucharova, M.D., Medizinische Universitätsklinik, Abteilung für Kardiologie, Auenbruggerplatz 15, A-8036 Graz, Austria; e-mail: [email protected] For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. ORIGINAL PAPERS, CLINICAL CARDIOLOGY J Clin Basic Cardiol 2001; 4: 54 Different Beta-Blocking Effects of Carvedilol and Bisoprolol to inclusion in the study subjects gave written informed con- Statistical analysis sent and underwent a short physical examination, ECG, and Results are given as arithmetic means ± 1 SD unless other- determination of routine laboratory parameters to ensure wise indicated. Significances of differences within groups current health. In particular, subjects with obstructive pul- were calculated using Repeated Measures ANOVA (Friedman’s monary disease, diabetes mellitus, peripheral arterial disease, Repeated Measures ANOVA on Ranks when applicable) and AV-block, bradycardia (resting heart rate < 50/min) or hypo- Student-Newman-Keuls test for post-hoc testing. A p-value tension (blood pressure < 100/70 mmHg) were excluded. < 0.05 was considered statistically significant On each day of the study, subjects entered the laboratory between 7 and 9 a.m. following an overnight fast. The blinded study medication was swallowed with 50–100 ml of water. Results Three hours later, exercise was performed for 10 min. on a bi- cycle ergometer at 70 % of mean individual work load. Heart Subjects were 33 ± 5 years of age, were 181 ± 8 cm in height rate and blood pressure were measured at rest immediately and weighed 74 ± 7 kg, and performed at 156 ± 13 Watts before the onset of exercise, during the last minute of exercise, over 10 min. on the bicycle ergometer. and at rest after 15 min. of recovery. Continuous ECG moni- Haemodynamic results are summarised in Table 1. At rest toring and cuff sphygmomanometry were used to record heart before exercise, increasing doses of bisoprolol caused a pro- rate and blood pressure. The investigation conforms with the gressive decrease in heart rate (63, 61 and 53 beats/min) principles outlined in the Declaration of Helsinki (Br Med J which was significantly different from placebo in all cases, 1964; II: 177) and was approved by the Ethics Committee of the whereas increasing doses of carvedilol caused increasing heart Faculty of Medicine, Karl Franzens University, Graz, Austria. rates (63, 63 and 68 beats/min) with the result obtained with 100 mg carvedilol failing to reach statistical significance from Materials placebo (Fig. 1); furthermore, 10 mg bisoprolol were signifi- (R,S)-bisoprolol and (R,S)-carvedilol were taken from formu- cantly more effective than 100 mg carvedilol (p < 0.05). lations commercially available in Austria (Concor® and Dila- Similar trends were observed at rest after 15 min. of recovery trend®, respectively). The blinded pharmaceutical formula- (Fig. 2); again, 10 mg bisoprolol were significantly more ef- tions (hard gelatine capsules) containing 25 mg (R,S)-carve- fective than 100 mg carvedilol (p < 0.05). During exercise, dilol, 50 mg (R,S)-carvedilol, 100 mg (R,S)-carvedilol, 2.5 mg both carvedilol and bisoprolol significantly decreased heart (R,S)-bisoprolol, 5 mg (R,S)-bisoprolol, 10 mg (R,S)-biso- rate compared to placebo (–17 %, –18 %, –21 % and –17 %, prolol, or placebo together with mannitol and carbosil as auxil- –21 %, –25 %, respectively) (Fig.